Metastasis is the leading cause of mortality in patients with epithelial cancers. This complex process involves the detachment of cells from the primary tumor, invasion into surrounding tissue, entrance to and survival within the bloodstream, extravasation, and, finally, survival and proliferation at the secondary site. It is believed that metastasis is an inefficient process. Clinically, metastatic inefficiency can be appreciated by considering that many tumors continuously shed cancer cells into the bloodstream on a daily basis, giving rise to a population of circulating tumor cells (CTCs), yet only a small number of these go on to colonize distant sites in a process which may take decades.
Some groups have reported that survival within the bloodstream and subsequent extravasation are completed efficiently by most tumor cells and that the ability to survive and grow at secondary sites is what determines the aggressiveness of a cell type [Luzzi, K. J., et al., Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol, 1998. 153(3): p. 865-73., Koop, S., et al., Fate of melanoma cells entering the microcirculation: over 80% survive and extravasate. Cancer Res, 1995. 55(12): p. 2520-3., Podsypanina, K., et al., Seeding and propagation of untransformed mouse mammary cells in the lung. Science, 2008. 321(5897): p. 1841-4., Tsuji, T., et al., Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth. Cancer Res, 2008. 68(24): p. 10377-86.]. In an effort to study the fate of CTCs, other groups have conducted studies to monitor the destination and viability of tumor cells injected systemically into mice. These authors concluded that the majority of circulating tumor cells are rapidly destroyed in the bloodstream by shear force [Fidler, I. J., Metastasis: quantitative analysis of distribution and fate of tumor embolilabeled with 125 I-5-iodo-2′-deoxyuridine. J Natl Cancer Inst, 1970. 45(4): p. 773-82., Fidler, I. J., Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Res, 1975. 35(1): p. 218-24.] and/or by deformation following size restriction in the microvasculature [Weiss, L., Deformation-driven, lethal damage to cancer cells. Its contribution to metastatic inefficiency. Cell Biophys, 1991. 18(2): p. 73-9., Weiss, L., et al., Lethal deformation of cancer cells in the microcirculation: a potential rate regulator of hematogenous metastasis. Int J Cancer, 1992. 50(1): p. 103-7.]. This led to the longstanding assumption that cell death within the circulation is a major contributor to metastatic inefficiency. Observations of significant cell loss following injection into mice have been reported by others as well [Kienast, Y., et al., Real-time imaging reveals the single steps of brain metastasis formation. Nat Med, 2010. 16(1): p. 116-22., Al-Mehdi, A. B., et al., Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med, 2000. 6(1): p. 100-2.].
During hematogenous dissemination, CTCs encounter a wide range of shear stresses (1-105 dyn/s) [Schneider, S. W., et al., Shear-induced unfolding triggers adhesion of von Willebrand factor fibers. Proc Natl Acad Sci U S A, 2007. 104(19): p. 7899-903., Reneman, R. S., T. Arts, and A. P. Hoeks, Wall shear stress—an important determinant of endothelial cell function and structure—in the arterial system in vivo. Discrepancies with theory. J Vasc Res, 2006. 43(3): p. 251-69.]. Shear stress is a major component of the vascular microenvironment and has important biological implications; for example, endothelial cells are fine-tuned to shear stress and variations in the magnitude or frequency of shear forces have effects on the signaling, gene expression, and survival of these cells [Malek, A. M., S. L. Alper, and S. Izumo, Hemodynamic shear stress and its role in atherosclerosis. JAMA, 1999. 282(21): p. 2035-42., Malek, A. and S. Izumo, Physiological fluid shear stress causes downregulation of endothelin-1 mRNA in bovine aortic endothelium. Am J Physiol, 1992. 263(2 Pt 1): p. C389-96.]. Shear stress has also been shown to induce changes in the gene expression and adhesive properties of both leukocytes and cancer cells [Okuyama, M., et al., Fluid shear stress induces actin polymerization in human neutrophils. J Cell Biochem, 1996. 63(4): p. 432-41., Avvisato, C. L., et al., Mechanical force modulates global gene expression and beta-catenin signaling in colon cancer cells. J Cell Sci, 2007. 120(Pt 15): p. 2672-82., Stroka, K. M. and H. Aranda-Espinoza, A biophysical view of the interplay between mechanical forces and signaling pathways during transendothelial cell migration. FEBS J, 2010. 277(5): p. 1145-58.]. Epithelial cells, from which carcinomas are derived, reside in environments with much lower shear stress than found in the bloodstream [Althaus, M., et al., Mechano-sensitivity of epithelial sodium channels (ENaCs): laminar shear stress increases ion channel open probability. The FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 2007. 21(10): p. 2389-99.]. It is thus reasonable to believe such cells would be particularly susceptible to destruction by hemodynamic shear forces, as compared to naturally circulating cells (i.e. red blood cells and leukocytes). One early study examined death of B16 melanoma cells subjected to shear stress using a viscometer [Brooks, D. E., The biorheology of tumor cells. Biorheology, 1984. 21(1-2): p. 85-91.]. This report showed dose-dependent killing of cells, however, the earliest viability time points analyzed were after one hour of shear stress exposure.